ABSTRACT Pompe disease is an inherited neuromuscular disorder caused by a deficiency of the enzyme acid ?- glucosidase, which results in progressive phrenic neuropathology. Since available enzyme replacement therapy does not treat this neuropathology, diaphragm/phrenic neuromuscular dysfunction ultimately leads to ventilatory insufficiency and ventilator dependence. Consequently, respiratory complications are the leading cause of mortality in Pompe disease. Diaphragm pacing is an alternative approach to treat critical ventilatory insufficiency, activating phrenic axons through intramuscular electrodes. Exciting preliminary data from patients with Pompe disease who have undergone diaphragm pacing suggests it may do more than replace the need for mechanical ventilation. It may have a rehabilitative effect on diaphragm/phrenic activity, restoring some independence from ventilatory support of any kind. While these initial findings are encouraging, pacing-induced neuromuscular plasticity has scarcely been studied. The fundamental hypothesis guiding this proposal is that diaphragm pacing is a novel rehabilitative tool to increase diaphragm/phrenic activity, thereby improving the capacity for independent tidal volume generation. In this way, diaphragm pacing may promote ventilator weaning in Pompe disease. We will recruit patients with Pompe disease who have undergone intramuscular pacemaker implantation to replace chronic mechanical ventilation, and then evaluate the rehabilitative effects of pacing over 12 weeks on diaphragm/phrenic neuromuscular activity and recovery of independent breathing ability. During spontaneous breathing and maximal voluntary efforts, we will investigate pacing effects on breathing function. In addition, direct recordings of human diaphragm EMG activity using an innovative application of the diaphragm intramuscular electrodes will enable longitudinal evaluations of diaphragm/phrenic activity. To test our central hypothesis, we propose two specific aims: 1) test the hypothesis that a single bout of diaphragm pacing has lasting effects on diaphragm/phrenic activation and ventilation, and 2) test the hypothesis that these effects accumulate over 12 weeks of repeated, daily diaphragm pacing sessions. This high risk/high impact proposal will evaluate diaphragm pacing as a rehabilitative tool to increase diaphragm/phrenic activity and improve independent breathing ability. This work will provide the first controlled, empirical evidence concerning the ability of diaphragm pacing to rehabilitate phrenic neuromuscular function in Pompe disease, and may have profound implications for the use of diaphragm stimulation in other clinical disorders that compromise breathing. Our hope is that data generated in this study will form the basis for a future mechanistic study of diaphragm pacing to promote ventilator weaning in neuromuscular disease.